Evaluation of Atopic Dermatitis Improvement Caused by Low-Level, Low-Frequency Pulsed Electromagnetic Fields.

This study aimed to evaluate the effectiveness of using low-level, low-frequency pulsed electromagnetic field (LLLF_PEMF) stimulation to improve atopic dermatitis induced by 2,4-dinitrochlorobenzene (DNCB). Twenty 6-week-old hairless mice were randomly divided into Normal (n = 5), PEMF 15 Hz (n = 5), PEMF 75 Hz (n = 5), and Sham (n = 5) groups. Following the onset of atopic dermatitis symptoms, PEMF groups (15 and 75 Hz) were stimulated with LLLF_PEMF (15 mT) for 8 h per day for 1 week. Sensory evaluation analysis revealed a significant difference between the PEMF 15 Hz group and Sham group (P < 0.05), but these differences were not visually obvious. While both the PEMF and Sham groups had atopic dermatitis lesions, lesion size was significantly smaller in the two PEMF groups than in the Sham group (P < 0.001). Additionally, changes in epithelial thickness because of skin inflammation significantly decreased for both PEMF groups, compared with the Sham group (P < 0.001). In conclusion, these results suggest that PEMF stimulation in vivo triggers electro-chemical reactions that affect immune response. © 2022 Bioelectromagnetics Society.

The histone H3-lysine 4-methyltransferase Mll4 regulates the development of growth hormone-releasing hormone-producing neurons in the mouse hypothalamus.

In humans, inactivating mutations in MLL4, which encodes a histone H3-lysine 4-methyltransferase, lead to Kabuki syndrome (KS). While dwarfism is a cardinal feature of KS, the underlying etiology remains unclear. Here we report that Mll4 regulates the development of growth hormone-releasing hormone (GHRH)-producing neurons in the mouse hypothalamus. Our two Mll4 mutant mouse models exhibit dwarfism phenotype and impairment of the developmental programs for GHRH-neurons. Our ChIP-seq analysis reveals that, in the developing mouse hypothalamus, Mll4 interacts with the transcription factor Nrf1 to trigger the expression of GHRH-neuronal genes. Interestingly, the deficiency of Mll4 results in a marked reduction of histone marks of active transcription, while treatment with the histone deacetylase inhibitor AR-42 rescues the histone mark signature and restores GHRH-neuronal production in Mll4 mutant mice. Our results suggest that the developmental dysregulation of Mll4-directed epigenetic control of transcription plays a role in the development of GHRH-neurons and dwarfism phenotype in mice.

A case of latanoprost-induced diffuse facial skin hyperpigmentation.

INTRODUCTION: Latanoprost is a prostaglandin F2α analogue, which has been used as a first-line drug for open-angle glaucoma. Common side effects of latanoprost include hyperpigmentation. While it usually occurs on irides or periocular skin, diffuse facial hyperpigmentation is rarely reported. CASE PRESENTATION: A 71-year-old woman was presented with diffuse gray-brown colored maculopatches on her face. The symptom appeared 1 week after she started to use latanoprost eye drops for glaucoma. Biopsy specimen revealed vacuolar degeneration of dermo-epidermal junction and pigment incontinence in dermis. OBJECTIVE: The aim of this paper is to introduce a rare adverse effect of latanoprost and effective way of treatment. METHODS: We stopped her from using latanoprost. She was also treated with 532-nm potassium titanyl phosphate laser and low-fluence 1064-nm Q-switched Nd:YAG laser, while using topical agents. RESULT: After 10 weeks, we observed hyperpigmentation of her face was effectively and safely treated. The patient was satisfied with the result. CONCLUSION: Diffuse facial pigmentation could be one of the latanoprost-induced adverse effects and the laser treatments with topical agents we used can make it improve faster.

Dibenzoylmethane exerts metabolic activity through regulation of AMP-activated protein kinase (AMPK)-mediated glucose uptake and adipogenesis pathways.

Dibenzoylmethane (DBM) has been shown to exert a variety of beneficial effects on human health. However, the mechanism of action is poorly understood. In this study, DBM increased phosphorylation of AMP-activated protein kinase (AMPK) and stimulated glucose uptake in a skeletal muscle cell line. Both knockdown of AMPK with siRNA and inhibition with AMPK inhibitor blocked DBM-induced glucose uptake. DBM increased the concentration of intracellular calcium and glucose uptake due to DBM was abolished by STO-609 (a calcium/calmodulin-dependent protein kinase inhibitor). DBM stimulated phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), which was blocked by pretreatment with compound C, an AMPK inhibitor. The expression of glucose transporter type 4 (GLUT4) was increased by DBM. The translocation of GLUT4 to the plasma membrane was also increased by DBM in AMPK dependently. In addition, DBM suppressed weight gain and prevented fat accumulation in the liver and abdomen in mice fed a high-fat diet. In pre-adipocyte cells, DBM decreased the activity of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of fatty acid synthesis. Expression of the adipogenic gene, fatty acid synthase (FAS), was suppressed by DBM in an AMPK-dependent manner. These results showed that the beneficial metabolic effects of DBM might be due to regulation of glucose uptake via AMPK in skeletal muscle and inhibition of adipogenesis in pre-adipocytes.

Rhus verniciflua extract modulates survival of MCF-7 breast cancer cells through the modulation of AMPK-pathway.

Rhus verniciflua STOKES (RVS) is used as an anti-cancer agent in traditional herbal medicine. However, the underlying molecular mechanism of its action is poorly understood. Here, we elucidated the mechanism of the anti-cancer mechanism of RVS in MCF-7 human breast cancer cells. We found that RVS increased the phosphorylation of AMP-activated protein kinase (AMPK) and downstream acetyl-CoA carboxylase (ACC) and suppressed cell viability in an AMPK-dependent fashion. RVS also induced an increase in reactive oxygen species (ROS) levels. RVS-induced AMPK phosphorylation was not observed in the presence of N-acetyl-cysteine (NAC), which indicated that ROS is associated with RVS-induced AMPK phosphorylation. In addition, fluorescent staining (Annexin V/propidium iodide) revealed that RVS increased the expression of Annexin V, which indicates that RVS leads to cancer-induced apoptosis. Moreover, RVS increased the phosphorylation of p53 and the expression of Bax. The inhibition of AMPK blocked RVS-induced p53 phosphorylation and Bax expression, which suggests that AMPK is involved in RVS-induced cancer apoptosis. Taken together, these results demonstrate that RVS has anti-tumor effects on MCF-7 cells through an AMPK-signaling pathway.

Control of energy balance by hypothalamic gene circuitry involving two nuclear receptors, neuron-derived orphan receptor 1 and glucocorticoid receptor.

Nuclear receptors (NRs) regulate diverse physiological processes, including the central nervous system control of energy balance. However, the molecular mechanisms for the central actions of NRs in energy balance remain relatively poorly defined. Here we report a hypothalamic gene network involving two NRs, neuron-derived orphan receptor 1 (NOR1) and glucocorticoid receptor (GR), which directs the regulated expression of orexigenic neuropeptides agouti-related peptide (AgRP) and neuropeptide Y (NPY) in response to peripheral signals. Our results suggest that the anorexigenic signal leptin induces NOR1 expression likely via the transcription factor cyclic AMP response element-binding protein (CREB), while the orexigenic signal glucocorticoid mobilizes GR to inhibit NOR1 expression by antagonizing the action of CREB. Also, NOR1 suppresses glucocorticoid-dependent expression of AgRP and NPY. Consistently, relative to wild-type mice, NOR1-null mice showed significantly higher levels of AgRP and NPY and were less responsive to leptin in decreasing the expression of AgRP and NPY. These results identify mutual antagonism between NOR1 and GR to be a key rheostat for peripheral metabolic signals to centrally control energy balance.

Calcium activation of the LMO4 transcription complex and its role in the patterning of thalamocortical connections.

Lasting changes in neuronal connectivity require calcium-dependent gene expression. Here we report the identification of LIM domain-only 4 (LMO4) as a mediator of calcium-dependent transcription in cortical neurons. Calcium influx via voltage-sensitive calcium channels and NMDA receptors contributes to synaptically induced LMO4-mediated transactivation. LMO4-mediated transcription is dependent on signaling via calcium/calmodulin-dependent protein (CaM) kinase IV and microtubule-associated protein (MAP) kinase downstream of synaptic stimulation. Coimmunoprecipitation experiments indicate that LMO4 can form a complex with cAMP response element-binding protein (CREB) and can interact with cofactor of LIM homeodomain protein 1 (CLIM1) and CLIM2. To evaluate the role of LMO4 in vivo, we examined the consequences of conditional loss of lmo4 in the forebrain, using the Cre-Lox gene-targeting strategy. The organization of the barrel field in somatosensory cortex is disrupted in mice in which lmo4 is deleted conditionally in the cortex. Specifically, in contrast to controls, thalamocortical afferents in conditional lmo4 null mice fail to segregate into distinct barrel-specific domains. These observations identify LMO4 as a calcium-dependent transactivator that plays a key role in patterning thalamocortical connections during development.

Tumor initiation inhibition through inhibition COX-1 activity of a traditional Korean herbal prescription, Geiji-Bokryung-Hwan, in human hepatocarcinoma cells.

Some Korean and oriental herbal prescriptions used for a syndrome expressed as chest paralysis and heartache are thought to be effective for angina pectoris. We investigated the effects of an oriental medicinal prescription, Geiji-Bokryung-Hwan (GBH) consisting of herbs of Cinnamomi Ramulus, Poria Cocos Hoelen (Pachymae Fungus), Moutan Cortex Radicis, Paeoniae Radix, and Persicae Semen, on growth-inhibitory activity and cancer chemopreventive activity in assays representing three major stages of carcinogenesis. The GBH was found to act as an potent inhibitor of cyclooxygenase (COX)-1 only but not as COX-2 inhibitor. Furthermore, the extract mediated anti-inflammatory effects and inhibited COX-associated hydroperoxidase functions (anti-promotion activity). Inhibitory effect of the GBH on the growth of cancer cell lines such as HepG2 cell and Hep3B cell was shown. These data suggest that GBH extracts merit investigation as a potential cancer chemopreventive agent in humans, especially in hepatological cancers.

A Korean herbal medicine, Panax notoginseng, prevents liver fibrosis and hepatic microvascular dysfunction in rats.

We assessed the prevention of hepatic fibrogenesis by water-extract of Panax notoginseng Buck F.H. Chen. (Arialiaceae) root (PNS) in Long-Evans rats with cinnamon coat color (LEC rats). LEC rats were divided into three groups A, fed on a basal diet (BD); B, fed on BD plus 1% PNS; and C), fed on BD plus 0.005% lycopene as a control. All rats were sacrificed at 26 weeks of age. The percentage of the total area involved by fibrosis was 1.46 +/- 0.47 in group A, 0.83 +/- 0.10 in B (P=0.0030, B vs A) and 0.91 +/- 0.45 in C (P=0.0035, C vs. A). The percentage of the total area that was stained for alpha-SMA was 0.56 +/- 0.34 in group A, 0.15 +/- 0.02 in B (P=0.0016, B vs. A and 0.11 +/- 0.01 in C (P=0.0025, C vs. A. In group B, malondialdehyde (MDA) in the liver was lower than in group C (P=0.007). In group C, the concentration of iron in the liver was lower than in group A (P=0.0053). Thus, PNS suppressed fibrogenesis through reduced generation of lipid peroxides. The mechanisms of this preventive effect of fibrogenesis with PNS were suggested to inhibit the stellate cell activity. Second objective of this study was to determine whether PNS affects hepatic microvascular dysfunction elicited by gut ischemia and reperfusion (I/R), since gut I/R causes hepatic microvascular dysfunction, and to investigate the role of nitric oxide (NO). Male Wistar rats were exposed to 30 min of gut ischemia followed by 60 min of reperfusion. Intravital microscopy was used to monitor the number of non-perfused sinusoids (NPS). In another set of experiments, PNS (1 g/kg per day intragastrically) was administered to rats for 7 days. In some experiments, dexamethasone (ST) (2 mg/kg per day intravenously) was administered. In control rats, gut I/R elicited increases in the number of NPS, and plasma TNF-alpha and ALT activities, and these changes were mitigated by the pretreatment with PNS. Pretreatment with an NO synthase inhibitor diminished the protective effects of PNS on the increase in NPS and plasma TNF-alpha levels, but not its effect on the increase in plasma ALT activities. Pretreatment with PNS increased plasma nitrite/nitrate levels. The responses caused by gut I/R were attenuated by the pretreatment with ST. Pretreatment with an NO synthase inhibitor did not affect the effect of ST. These results suggest that PNS attenuates the gut I/R-induced hepatic microvascular dysfunction and inflammatory responses such as TNF-alpha production in the early phase via enhancement of NO production, and sequential hepatocellular damage via its anti-inflammatory effect.